Thyroid stimulating hormone receptor(TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease(GD).However,the association between TSHR gene polymorphism and the risk of GD rema...Thyroid stimulating hormone receptor(TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease(GD).However,the association between TSHR gene polymorphism and the risk of GD remains controversial.In this study,we investigated the relationship between the two conditions by meta-analysis.We searched all relevant case-control studies in PubMed,Web of Science,CNKI and Wanfang for literature available until May2015,and chose studies on two single nucleotide polymorphisms(SNPs):rs 179247 and rsl2101255,within TSHR intron-1.Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure,and publication bias was examined by modified Begg's and Egger's test.Eight eligible studies with 15 outcomes were involved in this meta-analysis,including 6,976 GD cases and 7,089 controls from China,Japan,Poland,UK and Brazil.Pooled odds ratios(ORs) for allelic comparisons showed that both TSHR rsl79247A/G and rsl2101255T/C polymorphism had significant association with GD(OR=1.422,95%CI=1.353—1.495,P〈0.001,P_(heterogeneity)=0.448;OR= 1.502,95%CI:1.410-1.600,P〈0.001,P_(heterogeneity)=0.642),and the associations were the same under dominant,recessive and co-dominant models.In subgroup analyses,the conclusions are also consistent with all those in Asian,European and South America subgroups(P〈0.001).Our meta-analysis revealed a significant association between TSHR rsl79247A/G and rsl2101255T/C polymorphism with GD in five different populations from Asia,Europe and South America.Further studies are needed in other ethnic backgrounds to independently confirm our findings.展开更多
During the pathogenesis of type 1 diabetes(T1D) and type 2 diabetes(T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compens...During the pathogenesis of type 1 diabetes(T1D) and type 2 diabetes(T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet(HFD) and streptozotocin(STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of isletβ cells. Cre-LoxP systems were used to generate islet cell type-specific(α, β, or δ) green fluorescent protein(GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing(scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into α or δ cells in both youth-and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice(both youthand adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these “α or δ” cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.展开更多
Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This ...Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobin A1 c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1 DM patients(duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1 DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.81102032)
文摘Thyroid stimulating hormone receptor(TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease(GD).However,the association between TSHR gene polymorphism and the risk of GD remains controversial.In this study,we investigated the relationship between the two conditions by meta-analysis.We searched all relevant case-control studies in PubMed,Web of Science,CNKI and Wanfang for literature available until May2015,and chose studies on two single nucleotide polymorphisms(SNPs):rs 179247 and rsl2101255,within TSHR intron-1.Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure,and publication bias was examined by modified Begg's and Egger's test.Eight eligible studies with 15 outcomes were involved in this meta-analysis,including 6,976 GD cases and 7,089 controls from China,Japan,Poland,UK and Brazil.Pooled odds ratios(ORs) for allelic comparisons showed that both TSHR rsl79247A/G and rsl2101255T/C polymorphism had significant association with GD(OR=1.422,95%CI=1.353—1.495,P〈0.001,P_(heterogeneity)=0.448;OR= 1.502,95%CI:1.410-1.600,P〈0.001,P_(heterogeneity)=0.642),and the associations were the same under dominant,recessive and co-dominant models.In subgroup analyses,the conclusions are also consistent with all those in Asian,European and South America subgroups(P〈0.001).Our meta-analysis revealed a significant association between TSHR rsl79247A/G and rsl2101255T/C polymorphism with GD in five different populations from Asia,Europe and South America.Further studies are needed in other ethnic backgrounds to independently confirm our findings.
基金supported by the National Natural Science Foundation of China(81830023,82070803,82100838,82100837,81900708)。
文摘During the pathogenesis of type 1 diabetes(T1D) and type 2 diabetes(T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet(HFD) and streptozotocin(STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of isletβ cells. Cre-LoxP systems were used to generate islet cell type-specific(α, β, or δ) green fluorescent protein(GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing(scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into α or δ cells in both youth-and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice(both youthand adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these “α or δ” cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.
基金supported by the National Natural Science Foundation of China(81270897,81300668,81370939,81400813,81400808,81530026,81370922)the Jiangsu Provincial Special Program of Medical Science(BL2012026)the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions support this study
文摘Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobin A1 c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1 DM patients(duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1 DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.